The overall aim of this proposal is to support the continuing development of the applicant as a scientist in the field of drug abuse treatment. The applicant's program of research is driven by two main themes: 1) That pharmacotherapies may be developed by considering the heterogeneity of drug addicted samples and targeting interventions to specific subgroups; and 2) That the efficacy of medications may be enhanced by developing combined behavioral and pharmacologic interventions and by examining the implications of initial abstinence during a placebo lead-in upon medication effects. During the proposed K02, the applicant will serve as principle investigator on four main projects: I.) A placebo-controlled trial of venlafaxine for cocaine abusers with depressive disorders (P50 DA09236, Project 3); II.) A Stage I project to develop a behavioral therapy for depression in opiate dependent patients based on operant theory (R01 DA13118); III.) Cocaine medication development trials examining the efficacy of the NMDA antagonist memantine and the GABA enhancer gabapentin, and also examining the impact of abstinence during an initial placebo lead-in upon demonstration of medication effects (P50 DA12761, Project 1); and IV.) A controlled trial testing the efficacy of a behavioral therapy designed to improve the success of oral naltrexone maintenance for opiate dependence, and simultaneously testing the efficacy of an initial injection of a long-acting depot naltrexone formulation in improving retention in naltrexone maintenance treatment (R01 DA10746). The applicant will continue to assume a leadership role in the Department in mentoring young investigators, including junior colleagues on the above projects and research fellows. These mentorships extend the applicant's main research themes, for example addressing the treatment implications of comorbid disorders other than depression (e.g. attention deficit disorder, impulsive aggression, pathological gambling) and seeking opportunities for early intervention in children and adolescents at high risk for drug abuse. The applicant will continue to pursue a training plan focused on methodology and statistics of clinical trials, behavioral interventions, and the responsible conduct of research.